On his return he was enrolled as an advocate and started his legal practice in civil law at Hulftsdorp.

Senanayake left his legal practice and entered mainstream politics in 1943, when he contested a by-election for the Naranwala electorate, which had been made vacate by the sudden death of his brother-in-law Siripala Samarakkody.

He initiated the Ceylonese enterprise in commerce that was dominated by Europeans in the British colonial era.

The Ceylon-China Rubber-Rice Pact, signed in 1952, which had a five-year term and renewable proved to be a cornerstone Ceylon foreign policy, establishing close relations with the People's Republic of China and Sri Lanka.

The pact was beneficial to Ceylon that depended on rice exports, but came into conflict with the pro-western government.

He continued to hold the post of Minister of Trade and Commerce under his cousin Sir John Kotelawala, who succeeded Dudley Senanayake.

With mounting differences of opinions, notably with tension mounting between United National Party strongman and distant relative J. R. Jayawardene, Senanayake resigned his Ministerial portfolio on 10 July 1954 and was later expelled from the United National Party.

He along with Philip Gunawardena, Minister for Agriculture and Food; was instrumental in convincing Bandaranaike to award the lucrative shipping contract to import rice from Burma and Thailand to the government own Ceylon Shipping Corporation and lucrative sugar manufacturing contract to the government Sugar Cooperation, preventing these going to companies created by Mapitigama Buddharakkitha Thero and his associate H. P. Jayawardene.

Following the assassination, Senanayake served under his successor W. Dahanayake as Minister of Food, Commerce and Trade.